A physically active lifestyle is an essential component of care in Chronic Obstructive Pulmonary Disease (COPD) to restore limb muscle function. However, patients with limited improvement after exercise (EXEC) training remain at increased risk for hospital admission and mortality. The potential of nutritional supplementation and anabolic drugs to enhance efficacy of EXEC training are inconclusive and/or have safety concerns. We recently observed that muscle dysfunction in COPD is associated with severe disturbances in the metabolism of the branched-chain amino acids, their keto acids, and ?-hydroxy ?-methylbutyric acid (HMB) and enhanced net protein loss 24 hours after high-intensity resistance EXEC (rEXEC), known to induce acute muscle hypoxia, in stable moderate to severe COPD (GOLD II-III) patients. As rEXEC is a key component of training in COPD, there is a critical need to identify the mechanisms of rEXEC induced metabolic deregulations, and the role of hypoxia via the HIF1?-mTOR pathway so that safe, clinically- and cost-effective therapies can be developed. Our overall objective is to identify the metabolic deregulations and molecular mechanisms underlying protein loss induced by rEXEC in COPD, and to evaluate the effectiveness of targeted nutritional supplementation alongside EXEC training. Our central hypothesis is that improving the metabolic and molecular responses to rEXEC via targeted essential amino acid modulation enriched with HMB (EAA+HMB) will increase muscle function in COPD patients more than EAA alone because of the anti-catabolic and prolonged anabolic properties of HMB. Also, recent data showed favorable effects of HMB on muscle contractility, aerobic capacity and EXEC regenerative capacity. In aim 1, we will identify the metabolic and molecular mechanisms by which rEXEC induces protein catabolism in well characterized COPD patients (GOLD II-III), known of their elevated risk for tissue hypoxia, muscle atrophy, and metabolic disturbances, versus healthy matched control subjects. We will use an innovative 15 stable tracer iv pulse approach to analyze metabolism of multiple amino acids including HMB in depth (metabolic profile), muscle protein synthesis/ breakdown, and the molecular mechanisms how rEXEC impairs skeletal muscle protein homeostasis. In aim 2, a randomized, double blind, placebo controlled, clinical trial will evaluate the efficacy of dietary EAA+HMB versus EAA supplementation versus placebo (reflecting standard of care) alongside 8 weeks of EXEC training to improve muscle strength (primary endpoint) and endurance, physical activity, well-being, and disease related- and global clinical outcomes in COPD (GOLD I-III). GOLD I is included as muscle dysfunction is already present and therefore timely therapeutic interventions are needed to achieve realistic behavioral changes. These results are expected to have an important positive impact because proof of principle demonstration of the effectiveness of a targeted nutritional formulation to be used alongside EXEC in COPD will provide strong justification for its continued development and future clinical trials to improve patient outcomes and to optimize current strategies to restore muscle function.